FORCES ON THE EVOLUTION AND BIOLOGY OF CLADE A HIV1

A HIV1 进化枝的进化和生物学的力量

• 批准号: 2794697
• 负责人: Mary L. Poss
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2794697
• 关键词: HIV envelope protein; antiviral antibody; biochemical evolution; clinical research; female; flow cytometry; genetic polymorphism; genetic strain; human immunodeficiency virus 1; human tissue; monoclonal antibody; recombinant virus; tissue /cell culture; virus genetics; virus replication

Genetic variation in the envelope gene of HIV-1 results in biological changes in the virus. Globally, HIV-1 has been classified into eleven distinct viral clades, designated A-J, and O, based on phylogenetic properties of envelope genes. The best characterized viral clade, clade B, is the dominant HIV-1 subtype found in the Americas and Europe. Over 60 percent of infections with HIV-1, however, occur in sub-Saharan Africa. Multiple clades are found in African populations, including clades A, C, and D and the highly divergent clade O. Infections with clade A are most common throughout western, central and east Africa. Because the envelope gene contributes important features to viral phenotype, it is likely that clade-specific properties exist. The paradigm for HIV-1 pathogenesis and the strategies for therapeutic intervention are, however, based on HIV-1 clade B viruses. Models of early infection dynamics presuppose that an infection is initiated by a single viral variant that diversifies over time in response to selection pressures in the new host. As the virus diversifies, variants emerge which are phenotypically different than the founder population. This pattern of events may be more complex in African women because multiple variants are present in many individuals at seroconversion. The extent of diversity (2-5.5 percent) found in women are seroconversion is generally not achieved in an individual infected with a single variant until several years after infection. Because more than 50 percent of HIV-1 infections in Africa involve women, it will be important to characterize variants found at the time that infection is detected in African women to determine if properties of individual variants, or interaction among variants, may influence pathogenic potential of the viral population. The proposed experiments will test the hypothesis that (1) distinct genetic variants identified at seroconversion in clade A infected women will have different biological potentials (2) and that interaction between variants may lead to an evolutionary course that differs from that defined by studies of individual variants. AIMS: (1). Viruses will be constructed and characterized that contain envelope genes from the heterogeneous seroconversion population of clade A HIV-1 infected women. (2) The ability of monoclonal antibodies to gp120 to recognize clade A variants will be determined, and the affect of antibodies on replication kinetics of the viruses will be assessed. (3) The genetic and phenotypic features of viruses that evolve in individual and in mixed cultures under antibody selection will be determined. (4) Structural models of clade A seroconversion envelope glycoproteins will be determined by homology modeling.

HIV-1 包膜基因的遗传变异导致病毒发生生物学变化。 在全球范围内，根据包膜基因的系统发育特性，HIV-1 已被分为 11 个不同的病毒进化枝，分别命名为 A-J 和 O。 特征最鲜明的病毒进化枝 B 进化枝是美洲和欧洲发现的主要 HIV-1 亚型。 然而，超过 60% 的 HIV-1 感染发生在撒哈拉以南非洲地区。 非洲人群中发现了多个分支，包括分支 A、C 和 D 以及高度分化的分支 O。分支 A 的感染在西非、中非和东非最常见。由于包膜基因对病毒表型具有重要特征，因此很可能存在进化枝特异性特性。然而，HIV-1 发病机制的范式和治疗干预策略是基于 HIV-1 B 分支病毒。 早期感染动力学模型假定感染是由单一病毒变体引发的，该变体随着时间的推移而多样化，以响应新宿主的选择压力。 随着病毒的多样化，出现了与原始群体在表型上不同的变体。 这种事件模式在非洲女性中可能更为复杂，因为许多个体在血清转化时存在多种变异。 在女性中发现的多样性程度（2-5.5%）通常在感染单一变体的个体中要在感染几年后才能实现。 由于非洲 50% 以上的 HIV-1 感染涉及女性，因此表征在非洲女性中检测到感染时发现的变异非常重要，以确定个体变异的特性或变异之间的相互作用是否可能影响致病潜力病毒群体。 拟议的实验将检验以下假设：(1) 在进化枝 A 感染女性中，在血清转化时鉴定出的不同遗传变异将具有不同的生物潜力 (2)，并且变异之间的相互作用可能导致与个体研究定义的进化过程不同的进化过程。变体。目标：(1)。 将构建并表征病毒，其中包含来自 A 分支 HIV-1 感染女性的异质血清转化群体的包膜基因。 (2)测定gp120单克隆抗体识别A进化枝变体的能力，并评估抗体对病毒复制动力学的影响。 (3) 将确定在抗体选择下在个体和混合培养物中进化的病毒的遗传和表型特征。 (4)通过同源建模确定进化枝A血清转化包膜糖蛋白的结构模型。